Andrew D. A. C. Smith

Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother–offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.

A comparison of dietary patterns derived by cluster and principal components analysis in a UK cohort of children

Background/Objectives:The objective of this study was to identify dietary patterns in a cohort of 7-year-old children through cluster analysis, compare with patterns derived by principal components analysis (PCA), and investigate associations with sociodemographic variables.Subjects/Methods:The main caregivers in the Avon Longitudinal Study of Parents and Children (ALSPAC) recorded dietary intakes of their children (8279 subjects) using a 94-item food frequency questionnaire. Items were then collapsed into 57 food groups. Dietary patterns were identified using k-means cluster analysis and associations with sociodemographic variables examined using multinomial logistic regression. Clusters were compared with patterns previously derived using PCA.Results:Three distinct clusters were derived: Processed (4177 subjects), associated with higher consumption of processed foods and white bread, Plant-based (2065 subjects), characterized by higher consumption of fruit, vegetables and non-white bread, and Traditional British (2037 subjects), associated with higher consumption of meat, vegetables and full-fat milk. Membership of the Processed cluster was positively associated with girls, younger mothers, snacking and older siblings. Membership of the Plant-based cluster was associated with higher educated mothers and vegetarians. The Traditional British cluster was associated with council housing and younger siblings. The three clusters were similar to the three dietary patterns obtained through PCA; each principal component score being higher on average in the corresponding cluster.Conclusions:Both cluster analysis and PCA identified three dietary patterns very similar both in the foods associated with them and sociodemographic characteristics. Both methods are useful for deriving meaningful dietary patterns.

Live-Birth Rate Associated With Repeat In Vitro Fertilization Treatment Cycles

IMPORTANCE The likelihood of achieving a live birth with repeat in vitro fertilization (IVF) is unclear, yet treatment is commonly limited to 3 or 4 embryo transfers. OBJECTIVE To determine the live-birth rate per initiated ovarian stimulation IVF cycle and with repeated cycles. DESIGN, SETTING, AND PARTICIPANTS Prospective study of 156,947 UK women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. EXPOSURES In vitro fertilization, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers. MAIN OUTCOMES AND MEASURES Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted, and conservative cumulative live-birth rates were estimated, reflecting 0%, 30%, and 100%, respectively, of women who discontinued due to poor prognosis and having a live-birth rate of 0 had they continued. RESULTS Among the 156,947 women, the median age at start of treatment was 35 years (interquartile range, 32-38; range, 18-55), and the median duration of infertility for all 257,398 cycles was 4 years (interquartile range, 2-6; range, <1-29). In all women, the live-birth rate for the first cycle was 29.5% (95% CI, 29.3%-29.7%). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65.3% (95% CI, 64.8%-65.8%) of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes, the live-birth rate for the first cycle was 32.3% (95% CI, 32.0%-32.5%) and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (95% CI, 67.8%-68.9%). For women aged 40 to 42 years, the live-birth rate for the first cycle was 12.3% (95% CI, 11.8%-12.8%), with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (95% CI, 29.7%-33.3%). For women older than 42 years, all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner-related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference. CONCLUSIONS AND RELEVANCE Among women in the United Kingdom undergoing IVF, the cumulative prognosis-adjusted live-birth rate after 6 cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4.

Longitudinal comparisons of dietary patterns derived by cluster analysis in 7- to 13-year-old children

Little is known about changes in dietary patterns over time. The present study aims to derive dietary patterns using cluster analysis at three ages in children and track these patterns over time. In all, 3 d diet diaries were completed for children from the Avon Longitudinal Study of Parents and Children at 7, 10 and 13 years. Children were grouped based on the similarities between average weight consumed (g/d) of sixty-two food groups using k-means cluster analysis. A total of four clusters were obtained at each age, with very similar patterns being described at each time point: Processed (high consumption of processed foods, chips and soft drinks), Healthy (high consumption of high-fibre bread, fruit, vegetables and water), Traditional (high consumption of meat, potatoes and vegetables) and Packed Lunch (high consumption of white bread, sandwich fillings and snacks). The number of children remaining in the same cluster at different ages was reasonably high: 50 and 43% of children in the Healthy and Processed clusters, respectively, at age 7 years were in the same clusters at age 13 years. Maternal education was the strongest predictor of remaining in the Healthy cluster at each time point – children whose mothers had the highest level of education were nine times more likely to remain in that cluster compared to those with the lowest. Cluster analysis provides a simple way of examining changes in dietary patterns over time, and similar underlying patterns of diet at two ages during late childhood, that persisted through to early adolescence.

Model Selection of the Effect of Binary Exposures over the Life Course.

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Associations of folate, vitamin B12, homocysteine, and folate-pathway polymorphisms with prostate-specific antigen velocity in men with localized prostate cancer.

Background: Vitamin B12, holo-haptocorrin, and the folate-pathway single-nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer. Methods: We measured plasma folate, B12, holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K.-wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements. Results: Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B12, holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in loge concentration, 1.57; 95% confidence interval (95% CI), 0.98-2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y. Conclusions: We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer. Impact: Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication. Cancer Epidemiol Biomarkers Prev; 19(11); 2833–8. ©2010 AACR.

Nonparametric Regression on a Graph

The ‘Signal plus Noise’ model for nonparametric regression can be extended to the case of observations taken at the vertices of a graph. This model includes many familiar regression problems. This article discusses the use of the edges of a graph to measure roughness in penalized regression. Distance between estimate and observation is measured at every vertex in the L2 norm, and roughness is penalized on every edge in the L1 norm. Thus the ideas of total variation penalization can be extended to a graph. The resulting minimization problem presents special computational challenges, so we describe a new and fast algorithm and demonstrate its use with examples. The examples include image analysis, a simulation applicable to discrete spatial variation, and classification. In our examples, penalized regression improves upon kernel smoothing in terms of identifying local extreme values on planar graphs. In all examples we use fully automatic procedures for setting the smoothing parameters. Supplemental materials are available online.

External validation and calibration of IVFpredict: a national prospective cohort study of 130,960 in vitro fertilisation cycles

Background Accurately predicting the probability of a live birth after in vitro fertilisation (IVF) is important for patients, healthcare providers and policy makers. Two prediction models (Templeton and IVFpredict) have been previously developed from UK data and are widely used internationally. The more recent of these, IVFpredict, was shown to have greater predictive power in the development dataset. The aim of this study was external validation of the two models and comparison of their predictive ability. Methods and Findings 130,960 IVF cycles undertaken in the UK in 2008–2010 were used to validate and compare the Templeton and IVFpredict models. Discriminatory power was calculated using the area under the receiver-operator curve and calibration assessed using a calibration plot and Hosmer-Lemeshow statistic. The scaled modified Brier score, with measures of reliability and resolution, were calculated to assess overall accuracy. Both models were compared after updating for current live birth rates to ensure that the average observed and predicted live birth rates were equal. The discriminative power of both methods was comparable: the area under the receiver-operator curve was 0.628 (95% confidence interval (CI): 0.625–0.631) for IVFpredict and 0.616 (95% CI: 0.613–0.620) for the Templeton model. IVFpredict had markedly better calibration and higher diagnostic accuracy, with calibration plot intercept of 0.040 (95% CI: 0.017–0.063) and slope of 0.932 (95% CI: 0.839–1.025) compared with 0.080 (95% CI: 0.044–0.117) and 1.419 (95% CI: 1.149–1.690) for the Templeton model. Both models underestimated the live birth rate, but this was particularly marked in the Templeton model. Updating the models to reflect improvements in live birth rates since the models were developed enhanced their performance, but IVFpredict remained superior. Conclusion External validation in a large population cohort confirms IVFpredict has superior discrimination and calibration for informing patients, clinicians and healthcare policy makers of the probability of live birth following IVF.

Dietary patterns and changes in body composition in children between 9 and 11 years

Objective Childhood obesity is rising and dietary intake is a potentially modifiable factor that plays an important role in its development. We aim to investigate the association between dietary patterns, obtained through principal components analysis and gains in fat and lean mass in childhood. Design Diet diaries at 10 years of age collected from children taking part in the Avon Longitudinal Study of Parents and Children. Body composition was assessed using dual-energy X-ray absorptiometry at 9 and 11. Setting Longitudinal birth cohort. Subjects 3911 children with complete data. Results There was an association between the Health Aware (positive loadings on high-fiber bread, and fruits and vegetables; negative loadings on chips, crisps, processed meat, and soft drinks) pattern score and decreased fat mass gain in girls. After adjusting for confounders, an increase of 1 standard deviation (sd) in this score led to an estimated 1.2% decrease in fat mass gain in valid-reporters and 2.1% in under-reporters. A similar decrease was found only in under-reporting boys. There was also an association between the Packed Lunch (high consumption of white bread, sandwich fillings, and snacks) pattern score and decreased fat mass gain (1.1% per sd) in valid-reporting but not under-reporting girls. The main association with lean mass gain was an increase with Packed Lunch pattern score in valid-reporting boys only. Conclusions There is a small association between dietary patterns and change in fat mass in mid-childhood. Differences between under- and valid-reporters emphasize the need to consider valid-reporters separately in such studies.

Programming of adiposity in childhood and adolescence: associations with birth weight and cord blood adipokines

Context: Exposure to maternal adiposity during pregnancy is associated with higher offspring birth weight and greater adiposity through childhood and adult life. As birth weight reflects the summation of lean and fat mass, the extent to which fat mass at birth tracks into later life is unknown. Objective: To determine whether fat mass at birth is associated with child and adolescent adiposity. Design, Setting, and Participants: UK birth cohort with markers of neonatal fat mass; cord blood leptin, adiponectin, and birth weight and adiposity outcomes at age 9 (n = 2775) and 17 years (n = 2138). Main Outcomes: Offspring body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry–determined fat mass, and obesity at age 9 and 17 years. Results: Higher cord blood leptin was associated with higher z scores of fat mass [difference in mean per 10 pg/mL: 0.03 standard deviation (SD); 95% confidence interval (CI), 0.00 to 0.06], waist circumference (0.04 SD; 95% CI, 0.00 to 0.07), and BMI (0.04 SD; 95% CI, 0.00 to 0.08) at age 9. However, by age 17 the adjusted results were attenuated to the null. Cord blood adiponectin was not associated with measures of adiposity at age 9. At age 17, cord blood adiponectin was positively associated with fat mass (0.02 SD per 10 &mgr;g/mL; 95% CI, 0.02 to 0.03) and waist circumference (0.04 SD per 10 &mgr;g/mL; 95% CI, 0.03 to 0.05). Birth weight was positively associated with waist circumference (0.03 SD per 100 g; 95% CI, 0.02 to 0.04) and BMI (0.02 SD per 100 g; 95% CI, 0.00 to 0.03), but not fat mass or odds of obesity. Cord blood leptin and adiponectin were not associated with obesity at either age. Conclusions: Increased cord blood leptin and adiponectin, known surrogates of fetal fat mass, were weakly associated with increased fat mass in late childhood and adolescence, respectively.